Process for the manufacture of a-nor-b-homo-steroids



United-States Patent Oflice 3,522,157 Patented July 28, 1970 No Drawing. Application July 14, 1964, Ser. No. 382,643, a

which is a continuatiomin-part of application Ser. No. 266,524, Mar. 20, 1963. Divided and this application July 8, 1969, Ser. No. 840,053 Claims priority, application Switzerland, Mar. 23, 1962, 3,533/ 62 Int. Cl. B01j N10 US. Cl. 204-158 3 Claims ABSTRACT on THE DISCLOSURE A-nor-B-homo-steroids are prepared by irradiating 3- oxo-4,5-oxido-steroids with ultraviolet light.

CROSS-REFERENCES TO RELATED APPLICATIONS This is a division of our application Ser. No. 382,643, filed July 14, 1964, which itself is a continuation-in-part of our application Ser. No. 266,524, filed Mar. 20, 1963 now abandoned.

BACKGROUND OF THE INVENTION The present invention relates to a new process of manufacture of A-nor-B-homo-steroids, more particularly 3-oxoand 3:6-dioxo-A-nor-B-homo-steroids, starting from 3-oxo-4z5-oxidosteroids. The new compounds of this class are biologically active or represent intermedi ates for the manufacture of biologically active compounds. Such are e.g. the 3:6-dioxo-A-nor-B-homoandrostanes and -A -androstenes, which have in position 17/3 a free or esterified hydroxyl group, and also the corresponding 3-mono-oxo-compounds; they display a high anabolic activity coupled with a very low androgenic activity. The 3:6 dioxo A-nor-B-homopregnane compounds, more especially those which contain in position ,20, and possibly in position 11, an oxo group, in positions 17 and/or 21 and 116 hydroxyl groups, are of very special importance as novel compounds having a progestative or anti-inflammatory action respectively. Other compounds, such as the A-nor-B-homo-steroids of the androstane and pregnane series, which have substituents which might be converted into those named above typical for the biologically active compounds, are important as intermediates for said active compounds. This also applies to the other steroid series such as the A-nor-B- homo-steroids of the cholane, cholestane, spirostane,

cardanolide, and bufanolide series. They may be transformed in a manner known per se into the active compounds of the androstane and pregnane series, for example, by an acylolytic, oxidative or microbiological method.

The hitherto known steroids having the A-nor-B-homo skeletonnamely 6-oxo-A-nor-B-homocholestane and 6 x0 17,B-hydroxy-aand -5;9-A-nor-B-homo-androstane and their 17-benzoateswere obtained by basic treatment of the corresponding 4a-tosyl0xy-5a-hydroxy compounds.

SUMMARY OF THE INVENTION It has been found that A-nor-B-homosteroids can be obtained in a novel and simpler manner by irradiating 3-oxo-4:5-oxidosteroids with ultra-violet light and, if desired, converting the resulting 3:6'diox0-A-nor-B-homosteroids into their functional derivatives and/or metal salts, or by hydrogenating resulting A -3-oxo-6-acyloxy- A-nor-B-homosteroids.

The present process is illustrated, for example, by the following scheme of partial formulae:

The 3-OXO-4a25aand 45:55-oxidosteroids, saturated inpositions 1 and 2, used as starting materials can be prepared in the manner known per se from the corre sponding A -3-oxo compounds, for example by treatment with alkaline hydrogen peroxide or per-acids, or by hydrogenation of A 3 oxo 4:5-oxidosteroids. The lastmentioned starting materials are new; surprisingly, they can be obtained directly from A -3-oxosteroid-dienes by treatment with per-acids, for example with organic peracids, such as lower aliphatic or aromatic per-acids, for example with peracetic, perbenzoic and monoperphthalic acid,-or by dehydrogenation of the above-mentioned 1:2- saturated 3-oxo-4:5-oxid0steroids, for example with selenium dioxide-or dicyanO-dichloroquinone.

The irradiation according to the invention of 3-ox0- 4:5-oxidosteroids is advantageously performed in an organic solvent, for example in an aliphatic or cycloaliphatic hydrocarbon such as pentane, hexane or methylcyclohexane. Particularly suitable are aliphatic and cyclic ethers such, for instance, as diethyl ether or dioxane.

Suitable light is artificial or strong natural light; itis advantageous to use ultra-violet light such as is emitted by mercury low-pressure or high-pressure burners, or strong sunlight. The irradiation is advantageously performed at a temperature ranging from 0 to C.

In the 3:6-diox0-A-nor-B-homosteroids obtained as reaction products, which, being B-diketo compounds: are predominantly present in the enol form, any present ester or protective groups such, for example, as ketals, or hismethylenedioxy groups, may be. split hydrolyticallyand free hydroxyl groups may be oxidized to oxo groups. On the other hand, the products of the present process may be converted in the known manner into their functional ketone derivatives derived from the enol'form, or into metal salts. Thus, for example, acylation (for example treatment with a carboxylic anhydride, such as acetic or propionic anhydride) yields the corresponding enol esters; with etherifying agents such, for'example, as alco hols or thio-alcohols in the presence of an acidcatalyst, the enolethers and, respectively, thioenolethers are obtained. When the products of the present process are reacted, for example with hydrazines, cyclic hydrazones are obtained which may also be looked upon as pyrazole derivatives. Reaction with cupric salts furnishes the corresponding copper complexes.

The A 3 oxo-6-acyloxy-A-nor-B-homosteroids prepared by the present process can be converted into the corresponding saturated 6-unsub stituted 3-oxo-A-nor-B- homosteroids by catalytic hydrogenation in a manner known per so, such as hydrogenation, for example, in benzene or alcohol, with palladium carbon or palladiumbarium carbonate catalyst.

The 3-OXQ-4otC50tand 418:5fi-oxidosteroids used as starting materials in the present process belong preferably to the androstane, pregnane, cholane, cholestane, spirostane or cardanolide series or to the corresponding 19-nor series and may contain, in addition to the aforementioned groupings, in one or more than one of the positions 1, 6, 7, 8, 9, 11, 12, 14, 15-21 further substituents such as alkyl (for example methyl) groups and/or halogen atoms, free or functionally converted oxo groups, or free, esterified or etherified hydroxyl groups. Furthermore, the starting materials may contain double bonds, more especially as mentioned above, between carbon atoms 1 and 2. It is also possible to use a mixture of the two 4:5-isomeric epoxides.

Particularly important starting materials are, for example, the following compounds:

3-oxo-4u Soc-OXidO- and -4[3 5 fl-oxido- 17 hydroxyandrostane and its esters,

3:17-dioxo-4m5a-oxidoand -4 8:5,8-oxidoandrostane and its 17-ethyleneketa1,

3-OXO-4at5ot-0Xid0- and -4fi:5B-oxido-17a-a1kyl-, -17aalkenyland 17a-alkinyl-17B-hydroxyandrostanes and their esters, such as, for example 3-oxo-4az5a-oxidoand -4/8:5fi-oxido 17,8 hydroxy-l7a-methyl-, 17aethy1-, -l7a-vinyl-, -17a-ethinyland -17e-allyl-androstane,

3 :20-dioxo-4a: Scz-OXidO- and 4,8: 5 3-oxidopregnane,

3 20-dioxo-4u 5a-oxidoand 4,8:5fi-oxido-17a-hydroxypregnane and their esters,

3:20-di0XO-4otI5oz-0Xid0- and -4}8z5fi-oxido-2l-hydroxypregnane and their esters,

3z20-dioxo-4ez5a-oxidoand -45:5B-oxido-17u:2l-dihydroxypregnane, their esters and 17:20;20:2l-bismethylenedioxy compounds,

3:20-dioxo-4uz5a-oxido and 4,8:5fi-oxido-l1fl: 1711:21- trihydroxypregnane, their esters and l7:20;20:21-bismethylenedioxy compounds, inter alia, for example, the lactone of A -3-oxo-4:5-oxido-l7fl-hydroxy-17a- (fl-carboxyethyD-androstene and the 1-dehydro-4z5- oxidotestololactone; furthermore the derivatives, unsaturated in positions 1 and 2, of the above compounds. The 17-oxo or 20-oxo compounds are advantageously used in the form of their 17-mon0ketals or ZO-monoketals.

The 3:6-dioxo-A-nor-B-homosteroids, obtained by the present process, and their functional derivatives such, for example, as their enolesters (derived from the tautomeric enol form) of organic, more especially lower aliphatic or aromatic carboxylic or sulfonic acids, such, for example, as acetic, propionic, butyric, benzoic, para-toluenesulfonic acid, and enolethers and enolthioethers, for example lower alkyl ethers and thioethers (such as methy1-, ethyland propyl-ether and thioether), especially the compounds of the Formulae I and II OR OR lower alkenyl lower alkinyl O R O R -H lower alkyl,

and

O-acyl E R and R for a member selected from the group consisting of H, lower alkyl and OR, R together with R; a member selected from the group consisting of 8CH-R and %12, for a member selected from the group consisting of =0, 8 lower alkylene, 9 and %R R:

for a member selected from the group consisting of H and O-R and R is a member selected from the group consisting of H, an acyl group, a hydrocarbon radical, X and Y each is a member selected from the group consisting of hydrogen and methyl, and the l-dehydro derivativies, tautomerio forms and the enol esters and ethers thereof, are pharmacologically valuable compounds or intermediates for the preparing of pharmacologically valuable compounds.

Thus the compounds of Formula I in which R.,, stands for a free or esterified or etherified hydroxyl group together with a hydrogen atom or a lower alkyl group exhibit a high anabolic action. When there is a lower alkyl group in 17u-position together with the 17fi-hydroxyl group, the anabolic action develops also upon peroral administration. These compounds are therefore suitable for use as medicaments for the treatment of all conditions requiring an increased protein synthesis, such as chronic loss in weight, post-operative and post-infection conditions, anorexia and osteoporosis, more especially in geriatry. Particularly suitable are the following compounds:

3 :6-dioxo-17p-hydroxy-A-nor-Bhomo-androstane and its esters,

3 :6-dioxo-17B-hydroxy- 17a-alkyl-A-n0r-B-homoandrostanes and their esters,

3 :6-dioxo-175-hydroxy-l7a-alkyl-A-nor-B-homooestranes and their esters,

and 7aa-lower alkyl derivatives of these compounds and the l-dehydro-derivatives of all these compounds. As

specific compounds there may be mentioned for instance:

the 3:6-dioxo-17 3-hydroxy-A-nor-B-homoandrostane the 3 :6-dioxo17B-acetoxy-A-nor-Bhomo-androstane the 3 :6-dioxo-17fi-isobutyryloxy-A-nor-B-homo-androstane the 3 :6-dioxo-17B-valerianyloxy-A-nor-B-homo-androstane the 3 :6-dioxo-17fl-undecenyloxy-A-norB-homo-androstane the 3 :6-dioxo-17pdecanoyloxy-A-nor-Bhomo-androstane the 3 6-dioxo-17p-(phenylpropionyloxy)A-nor-B-homoandrostane the A -3 6-dioxo-17 8-acetoxy-l-methyl-A-nor-B-homoandrostene the A -3 6-dioxo-17B-acetoxy-A-nor-Bhomo-oestrene the 3:6-dioxo-17/3-hydroxy-7au, 17a-dimethyl-A-nor-B- homo-androstane.

Outstanding anabolic properties have the compounds:

3': 6-dioxo-17,8-hydroxy-17a-methyl-A-nor-B-homoandrostane 3 6-dioxo-17B-hydroxy-17a-methyl-A-nor-B-homooestrane and the 3 6-dioxo-17fl-hydr0xy-7au, l7at dimethyl-A-nor-B-homooestrane and their l-dehydro-derivatives.

-restitution ofthe muscle-to the weight of that muscle in normal control animals.Suchcompleterestitution is attained with very small doses of the'substances toftthe present invention. For :instance, when 3:6-'dioxo.-1=7;3- hydroxy-17a-methyl-A-nor-B-homo androstane riS administered subcutaneously, theoptimal anabolicweffectcorrespending to said complete-restitution is .attained with-a dose of approximately 0,3 mg./lgg. daily, for days. The androgenic effect of-the= substance may similarly be measured by determining .the increase in weight. of the .involuted seminal vesicles of the castrated animals. To

compare the 'androgenioactivityof thesame susbtance with its anaboliceffect the optimalandrogenictdose,viz.

that provoking a complete weight restitution "of .the

seminal vesicles, as compared to the-controls, isevaluatednIn the above case of the 3:6-dioxo-l7fi-hydroxyd7amethyl-A-nor-B-homo-androstanethis androgenic: dose is 13 to timesihigher than the=optimal anabolicdose when the administration is effected by the subcutaneous route. This means that a verygood dissociation between anabolic and androgenic effect is present which is a ,pre-

requisite "for an ideal anabolic treatmentfilnthe other' compound mentioned above, the 3:6-dioxo-17B=hydroxy- 7aa- 17u-dimethyl-A-nor-B-homo-oestrane, 'these conditions. are still more favorable, the ratio between the 'dose eliciting the optimal androgenic effect 'and' the dose peliciting the optimal anabolic'effectbeing'about 100, whenthe substance is administered subcutaneously andabout 70 on peroral administration. The absolute value of the anabolic effect is extremelyhigh with thiscompound; the

optimal dose under the aforementionedexperimental conditions being 0.03 mgi/kg.'body weightdaily'for 15:days

when given subcutaneously an'dlLO mg./-kg. dailyfor'15 days when given orally.

Compounds of the above Formula I wherein R stands for a free or esterified or etherified hydroxyl group together with an unsaturated hydrocarbon-radical, especially a vinyl, allyl, ethinyl or propinyl group, which 'may also be halogenated,'e.g. fluorinate'd,--'show a gestagenic or ovulation inhibiting actionJEspecially active *are the oestrane compounds and theirl-dehydro derivatives, for

example A -3 6-Cll0XO-1713-l1Yd1'0XY-l70t-Vll'1Yland -1"Zu-ethinyl-A- nor-B-homo-androstene.and their esters and A -3:6- dioxo-17B-hydroxy-17e-vinyland -17a-ethinyl-A-nor- B-homo-oestrene and their esters.

Compounds ofFormula II above in which R stands for an oxogroup and R for a hydrogen atom, exhibita pronounced progestative action. .Special mention deserve Compounds of the above Formula II wherein'lR is a :free, .an esterifiedor etherifiedlhydroxyl andfR is .anoxo group are distinguished by their anti-inflammatory and glucocorticoid action and may thus be used in the treatment of inflammatory diseases of the-jointsand their surroundings, for example ,polyar'thritis, in acute and chronic rheumatic fever .and in the form r of creams .and

:tsalves in dermatology ,for -,the ,treatment of teczematof I .diverse origin. Especially active arein this respect 'compounds, ofthe formula wherein .R represents ..a lhydrogen atom ..,or .a ;me'th$ l group and :R ...is a free or esterifieid .h-yldroxyl group .as wellzas 6renol-esterstor 6 enole1thers thereof.. As specific compoundst-herelmaythe mentioned particularly the..A 3:6:11:20-- tetraoxo x21 dihydroxy A nor B- homogpregnene, its 1 lower,aliphatic,carboxylicaacid ...esters, .,such;=as' the acetate, the. trimethylacetate, the ,propionate, t-valerate caproate ..etc,., and .the i7-.-methylderivatives 26f {these compounds.

.All compounds of.Formulae Land'IIrabove mayzals o he employed ,in veterinary medicineeg. (3S ;-additives .to .animatfodder.

The acid radicalskin the ,above -mentionedte'sters are ,more zespecially those ,of aliphatic, cyeloaliphatic, ,araliphatic, .aroma'tieorf heterocyclic. carboxylic acids containing..1,to'l15. carbon-atomsj for example'formiates, acetates, propionates, lbutyrates, ltrimethylacetates, caproates, valerates, oenanthates, decanoates, undecylenates, .cy'clo- .pentylpropionates, hexahydrobenzoates, ,phenylpropionates, benzoates, 'furoates, trifluoracetatesethyl or methyl tcarbonates or the. like.

tEtherstare primarily. derived fromgaliphatic, analiphatic, cycloaliphatic or heterocyclic :alcohols,preferably'phaving from 1 to 8-.carbon-tatoms;for. example Lfronrmethanol, ethanol, propanol, benzlylialcohol, cyclopentanol ortetrahydropyranol.

".In the case of "3,6 dioxo-17B hydroxy A-nor;'B homoandrostaueor -oestrane.compoun'ds or their l-dehydroderivatives, .6-mono-esters and 6-mono-e'thers,. as derived from the-.enollform of. the steroids said, as well ,as 5 17- mono-esters or e'thers'or 6,l'7rdiesters,ordiethers.mayhe ,p'reparedfrom the. unesterified compouri'dsi Thus, for example, by acylation of a 3,6 'dioxo-17u-alkyl-17fl-hydroxyandrostane or oestrane compound, for example, by treatment with carboxylic acid anhydride such as acetic or propionic .auhydride .at room temperature, the 6-eno1- esters are obtained,.whereas, treatment withan etherifying ..agent,-;for example .an alcohol, such as,.-an. alkanol, infthe .presenceof anacidic catalyst gives rise tojthe. corresponding enolethers. To obtain vv6,17-diesters the acylationfis .preferablylperformed at elevated temperature.. Inthej,6,17- vTdiesters thusv obtained it is, possible to liberate. the 6-enol ester group by acid hydrolysis, thus rendering accessible the il7-monoesters. When there is no hydrocarbon in. 17a- ,position, the acylation afiords .preferab ly the 6,17m-diestersffrom which there tare.obtainedj6-monoresters zby mild alkalinehydrolysis. and 17-mono-esters by .acidic hydrolysis.

f From, 21 hydroxy-20-ketOrA-nOr-Behomo pregnane ,derivatives or their 1 dehydrorderivatives,.such as for instancetheabove named A -3,6,I1,20 tetraoxor17a;21-dihydroxy A-nor-B-homo-pregnene, there .are obtained, under mild condition, 21-esters =and,'then, after longer periods of acylation, the ,.6,21v-diesters. ',Infthe. latter it is possible tosaponify only [the 6-ester ,lgroup by acid hydrolysis, or. ohlythe'lZl-ester group by \mildaalkaline hydrolysisfThere can thus be preparedj6-..andQZI-monoesters as well as 6,21-diesters.

,The new ,lpharmacologically active compounds can;;be

used for the manufacture of pharmaceutical preparations. These contain said active compounds together with a solid or liquid medicinal excipient. More particularly the preparations of the present invention are characterized by the content of one of the new A-nor-B-homo-steroids. The preparations are made by as such known methods, for example, with the use of pharmaceutical organic or inorganic excipients, suitable for parenteral, enteral and particularly oral, or also topic administration. Suitable excipients are substances that do not react with the new compounds such, as for example, water, vegetable oils, benzyl alcohols, polyethylene glycols, gelatine, lactose, starch, magnesium stearate, talc, white petroleum jelly, cholesterol or other medicinal excipients. More especially, preparations are made which are suitable for parenteral administration, preferably solutions, above all oily or aqueous solutions: furthermore suspensions, emulsions or implants; for enteral administration there are also made tablets or dragees, and for local administration also ointments or creams. If desired the preparations may be sterilized or they may contain assistants such as preserving, stabilizing, Wetting or emulsifying agents, salts for regulating the osmotic pressure or buffers. They may also contain other therapeutically active compounds. They are prepared in the known manner. The content of the active substance in these preparations, such as of a tablet, is preferably 0.01-20 mg. or 0.03-50%, especially 0.1 to by weight. Said pharmaceutical preparations can be used in human or veterinary medicine.

The process is described more fully in the following examples. The ultra-violet absorption spectra have been established in ethanolic solutions and the specific rotations were measured in a chloroform solution in a tube of 10 cm. length.

The irradiation with ultra-violet rays is performed under nitrogen in a quartz vessel in which the source of light is centra ly disposed and which is cooled by means of water. The light sources used are low-pressure burners NK 6/20 (monochromatic light of wavelength 254 my) and high-pressure burners Q 81 (both manufactured by Quartzlampen GmbH, Hanau).

Unless otherwise indicated, working up of the reaction mixture is performed as follows: It is taken up in ether, the organic phase washed with water until neutral, and the ethereal solution is dried over anhydrous sodium sulfate and evaporated in a. rotary evaporator. Chroma tography is performed, unless otherwise stated, with the use of 30 times the weight of neutral alumina of activity H.

EXAMPLE 1 A mixture of grams of l-dehydrotestosterone acetate and a solution of perbenzoic acid in 130 ml. of chloroform (8.5 mg. per ml.) is kept for 4 days in the dark at room temperature. The reaction solution is then diluted with ether and agitated successively with aqueous solutions of potassium iodide and sodium thiosulfate. A partially crystalline crude product is obtained which is chromatographed on alumina. A 2:1-mixture of benzene and hexane elutes 3.6 grams of a crystalline fraction, while a lzl-mixture of benzene and ether elutes 7.5 grams of unchanged starting material.

The first fraction is recrystallized four times from acetone-i-hexane and furnishes 2.15 grams of A -3-oxo- 45:55 oxido 17B acetoxyandrostene. Constant melting point: 144-145 C. Optical rotation [a] =+250 (c.=l.02). Ultra-violet spectrum: A =232 m (log e=3.96). Infra-red spectrum (in chloroform): 11:1725, 1680, 1623, 1255 cm.-

After 2 recrystallizations from acetone+hexane and 8 from ethanol the mother liquor products furnish 130 mg. of A -3-oxo-4u:5ot-oxido-17B-acetoxyandrostene having a constant melting point of 139-141 C. Ultra-violet spectrum: X =227.5 mu (log e=4.02). Infra-red spectrum (in chloroform): 11:1722, 1677, 1612, 1256 cm.

8 EXAMPLE 2 stene are hydrogenated in the presence of 200 mg. of palladium black of 5% strength in 10 ml. of benzene. When the absorption of hydrogen (1 mol) ceases, the solution is filtered through Celit, evaporated under vacuum, and the residue is recrystallized from acetone-{- hexane. Melting point: 153-155 C. Ultra-violet spectrum: final absorption at 210 my (log e=3.36). Infra-red spectrum (in chloroform): 1 1725, 1260 cm.- Optical rotation [a] =-|131 (c.=1.85). As revealed by the mixed melting point and the infra-red spectrum the product is identical with authentic 3-oxo-4fiz5fi-oxido-l7fiacetoxyandrostane; melting point 153-155 C.; optical rotation [a] =+135 (c.=1.30).

EXAMPLE '3 30 mg. of A -3oxo-4a:5u-oxido-17fl-acetoxyandrostene are hydrogenated with 30 mg. of palladium black of 5% strength in 3.5 ml. of benzene as described in Example 2 for A -3-oxo-4fi:Sfl-oxido-l7fi-acetoxyandrostene. After crystallization from acetone+hexane the resulting product has a constant melting point at 164-165 C. Optical rotation [ab-=68 (c.=0.64). Ultra-violet spectrum: final absorption at 210 m (log 6:3.49). Infra-red spectrum (in chloroform): 11:1715, 1268 cmf EXAMPLE 4 A solution of 2.0 grams of A -3-oxo-4fl:5fl-oxido-17flacetoxyandrostene in 200 ml. of dioxane is irradiated for 40 hours with a low-pressure burner, and then evaporated under vacuum. In the thin-layer chromatogram [eluant: benzene-l-methanol 19:1] of the crystalline residue no starting material canbe detected. After three recrystallizations from methylene chloride+methanol there are obtained 1.60 grams of -A -3:6-dioxo17fl-acetoxy-A-nor- B-homoandrostene (constant melting point +171-172 C.). Ferric chloride test: positive. Optical rotation [a] =+98 (c.=0.65). Ultra-violet spectrum: A 239 m;t(log e=3.96), 3.11 m (log e=3.87). Infra-red spectrum: in chloroform: v=1730, 1670, 1618, 1260 cmf in nujol: v=l730, 1658, 1609, 1567 (weak), 1256 cm."

EXAMPLE 5 A solution of 380 mg. of A -3-oxo-4ot:5a-oxido-17flacetoxyandrostene in 100 ml. of dioxane is irradiated for 2 hours with a low-pressure burner and then evaporated under vacuum. In the thin-layer chromatogram [eluant: benzene-l-methanol 19:1] of the residue no starting material can be detected. By chromatography on silica gel with a 19:1-mixture of benzene and ether there are obtained 200 mg. of crystals which, after three recrystallizations from methylene chloride+methanol, melt at 164- 166 C. mg). Sublimation in a high vacuum at C. yields pure A -3:6-dioxo-17fi-acetoxy-A-nor-B-homoandrostene melting at 171-172 C. which, according to its mixed melting point, specific rotation [a] =+93 (c. =0.74) and infra-red spectrum, is identical with the photo product described above in Example 4.

EXAMPLE 6 450 mg. of A 3:6-dioxo-17fi-acetoxy-A-nor-B-homoandrostene are hydrogenated in the presence of 450 mg. of palladium black of 5% strength in 50 ml. of benzene. When the absorption of hydrogen has ceased 1 mol. after 30 minutes) the solution is filtered through Celit and the filtrate is evaporated under vacuum. The residue is chromatographed on silica gel. A 9: l-mixture of benzene and ether elutes 360mg. of crystals which, after three recrystallizations from methylene chloride+methanol, yield 310 mg. of 3:6-dioxo-17/3-acetoxy-A-nor-B-homoandrostane having a constant melting point of 154-156- C. Ferric chloride test: positive. Optical rotation [a] =+47 (c.=0.72). Ultra-violet spectrum: A

- stene in 120 "-ml. of dioxane are iirradiate'd 'for 54 hours 3522,1157 9 51 9 291m (log e="396)(Infra-redspeetrumimchloroform: v356-dioxtrI'IZFhydroXy AFnQr-B#homoandrostene which, u="172l,"16'41, '1 6O8,1'255 cm. after-three-recrystallizations from methanol, displays a constantsmelt ing point at 1'=5'6-159CaInfra-red spectrum "EXAMPLE 7 'qin Nuj-oi v=3560 161116121 "emr uOpticalrotation with -a'lowpressure burnergandthe solution'is then evapo- Max:240 311 rated under vacuum. "According to its thirf-layer chromat- (log e=3.91,33t8;2). ogram [eluantz 19:1-mixture of benzene andfirnethanol] the residue contains -star'ting material and about 25% of EXAMPLE 12 3 6 .17p sAs Frric 'Assoluti'on-iof 1 80'-mg.0f A -;3 :6.-dioxo-.l 7 8-acetoxy-A- chloride test: positive. Ultra-violet .spectrum: Ame-2 293 ethanol is mixed with (1 =3- .32 two compounds.; are verysdifiiwlt a solution of 0.5 gram of copper acetate andr2 grams of to separate by chromatography on.silica wgel. Benzene 'sPdlumiactateim (if-Water, whereupon the reacelutes only =35 mg.-of uniform -.crystals which,=after're+%15 "'tmmsolmi'ownturnsdnstantaneously green- After crystallization.from methylene-chloride+methanol,rxnelt mes it is Poured into Water and extracted with benzene- Uat 1544560 I CH Accordingztotheir,mixemmelfinglpoint, Evaporation of the organicphase under vacuum yields 94 infraq'ed Spectrum, 1 1 v mg. of green .crystals.Wh1ch,. acc0rd1ng totheir thin-layer (1 :431. and Specific .pmtatian \chromatogram Iieluant: benzenermethanol '19zl], are .c =0 64-) h are id tifi d. ith. h h d d 1 'lumfQrm. (Afte'rlthree"recrystallizationsfrom methylene ib dtj g l a 'chlori'dei-imethanolthere .are obtained '40 mg. of the I A copper complex of A 3:6 dioxo 17)3 acetoxy-A-'nor*B- EXAMPLE '8 homoan'drostene which decomposes at 300-310C.' Ultra- 450 mg. of 3-oxo-4flz5 3-oxido-17fl-acetoxyandrostane 'Vidlt SP max=" III/L 0g i in 100 ml. of-dioxane are irradiated for 2-hourswith a (10g5:4131)-'II1ffarfed'-SPectruminCh10f0f01'm1'v=1721, high-pressure burner, and the solution isthenevaporated ,"1260cm; under vacuum. The residue contains according to itsthinlayer chromatogramieluant: benzene-i-methanol 1921-], EXNMPLE 143 ultra-violet spectrum =29lamu; l0g e=36l) and "580'n1gsf3F6dioxoI7B-acetoxy-A nor-B homoandroferric chloride test (positive), about-45% .of 3-:-6-dioxo- 30 tstanerare acetylated'ffofZa daysat room temperaturein a l7/8-acetoxy-A nor=B-homoandrostaneand.is free'from llil-mixtureof acetic afihy ri e n pyri' in The starting -material. Chromatography on silica -'gel with actionsolutionis evaporated under vacuum and the crysbenzene-l-ether (921) furnishes 200 mg..of crystals which, Ltalline residue is (dissolved in a 9:1-mixture "of benafter three recrystallizations from methylene ch-lozene+ether"'and7filtered through silicagel, to yield A 3- ride+methanol, melt at 154-456 C. v(1G0 mg.-)'-and acn 0x0 6:1'7diacetoxy A nor B homoandrostene which, after cording to their mixed melting .point and infra-redspec- 3 .recrystallizations from .acetone-i-hexane, displays a trum are identical with the compound described in Exconstant melting pointat"14'71l'49 C. (425 mg.).'Ultraample 6. violet spectrum: k 254 hm (log e=3.87).'Infra-red EXAMPLE '9 spectrumflin.chloroform: 11:1'745/1720 (strong), 1638, '80 mg. of 3-oxo-4ot:5ouoxido-17fl-acetoxyaridrostane in 1160 "cmfk Optlcal rotatlon []D= 10 dioxane are irradiated in-an open quartzreactionvessel for 10 hours with a low-pressure burner, arid the solution .EXAMPLE 14 is then evaporated under vacuum. According to the ferric .lkssolution of 780 lmg..iof.3:'6+dioXo 17;8-acetoxy-A-norchloride test (positive), thin-layer chromatograrn"[eluar"1t: hornoandrostane lILrZOITIlL of etha-nolis mixed withla benzene-Frnethan'ol 1951] and ultra-violet spectrum JsolutionrrofL025vgnamfiofccopper acetatewand 2 grams of (M :293 m 1og e=3.41)' the-residue contains, inter -sod-ium -acetate inJZOsrnlu.ofwvater.Thesolution'immedialia, starting material as well as about 28% of thephoto arely".turns green-a nd after 15 minutes it-is poured into product described in Example 6."The"mixture' isdiflicult "water, andwithfibenzene"90. mg. of.2green crystalsare isoto separate; 'it is chromatographedfonsilica -gel, with lated which,--according totheir'thin-layer chromatogram benzene e'luting about 4 mg. of uniform c'rysta'ls'melt- [eluant benzene+rnethanol l95l],=are uniform. After ing at l54-156 C. 'Accor'ding'to its mixed'melting' point, having been recrystallized five .times from methylene infrared spectrum and ultra-violet spectrum :291 chloride+methanol the resulting copper complex of 3:6- m log e=3.97), the compound is identical'with 3*.6- dioxo 17 3 acetoxy-A=nor l3 homoandrostane decomposes dioxo 17f -acetoxy-Amor B homoandrostane. at 300-3 10 C. Ultra-violet spectrum: =31() m p (lOgE -=4.33), 2 59mp (10g e==3.'95).Infrauedspectrum "EXAMPLE 10 in chloroform: :v=1720,= 1 578,! 1415, 1260.;cmr4. 440 mg. of A 3:6-dioxo-17 9 acetoxy-A nonB homo- EXAMPLE 15 androstene are kept for 6 days at roomtemperature in 10 ml. of a lzl-mixture of aceticanhydride. and pyridine, mixturefiof iKOOnmg. of a3:6adioxo:17fi-hydroxy-A- The solution is then evaporated to drynessunder vacuum nof-B-homoandrostane, 24111- 50f 'hydfazme hydrate and and the crystalline residue is dissolved in 9:1 'benfof ethanolrisvheated ina bomb tube. for. 16 hours zene-l-ether and filtered through silica gel; to yield 350 C.- cooled solution is-thenevaporated ymg. of A -3-0xo-6:17/3-diacetoxy-A nor B-hornoandror-nesssundervaelmmranddheiresultlngwcrystals.(300:mg-) stadiene which, after three recrystal1izations=from acewhich according to y n hromatogram [elllanti 'tone-l-hexane, melts at'120121"C. 'Ferric chIOri'deteSt: T benzene+methan01 1] are uniform-are recrystallized negative, Optical otation =+103 (c 91) .U:1t twice from methanol, toyield-"thepyrazole derivative of violet spectrum: k 248 m (log e-=3.94).'Infra-red 'i y y fr -h0m0andf0stane spectrum in chloroform: 1755, l722,"1703,l 649, 1595, allconsmntfmehlngipmnt p f 1255, 1165 notation Eoifl- 5=+ 57 .(c.==0.52)..i1-nfrared spectrum-1n EXAMPLE 1 cchloroformzrv=3630, 3640, @1635 1cm.- (weak). .Ultra- 200 f 1 3 6 17 t A B h ":violetgspectrumzqt =l227 ma,(log-e=3 .74). mg. 0 A- lOXO- fi-ace oxy- -nor-' omo- 1 w {I j androstene are hydrolyzed for 24- hours at'roomtempera- EXAMPLE 16 -ture in5 ml. of'saturated methanolic potassiumcarbonate 3 ;grams .or 3-oxo'-4fi:5/3-oxido-l7/3-acetoxyandrostane :solution. Extraction with ether furnishesl5O mg. of.A -.,75 -ran'd/900: mg. ofiseleniumdioxide-are. mixed with v ml. of tertiary butanol and 1.5 ml. of glacial acetic acid. The suspension is refluxed for 24 hours under nitrogen, then another 900 mg. of selenium dioxide are added and the whole is boiled for 24 hours longer. The cooled solution is freed by decantation from the precipitated selenium, evaporated and the residue is dissolved in ethyl acetate. The organic solution is washed successively with dilute potassium bicarbonate solution, water, a freshly prepared ice-cold ammonium sulfide solution, ice-cold dilute ammonia solution, and water. After several recrystallizations from acetone+hexane there are obtained 2 grams of A -3-oxo-4B:5 8-oxido-17 3 acetoxyandrostene melting at 144-145 C.

In an analogous manner 4fi:5,B-epoxy-19 nortestosterone acetate yields 1-dehydro-4p:5,8-epoxy-19-nortestosterone acetate.

EXAMPLE 17 9 grams of A -3-oxo-17u-methyl-175-hydroxyandrostadiene in a solution of perbenzoic acid in 140 ml. of chloroform (35 mg. per ml.) are kept for 4 days in the dark at room temperature. The reaction solution is then diluted with ether and agitated with aqueous potassium iodide solution and then with aqueous sodium thiosulfate solution, to yield 9.1 grams of a crude product which is chromatographed on neutral alumina (activity III; 30 times the amount).

Benzene and a 9:1-mixture ofv benzene+ether elute 1830 mg. of amorphous material which is once more chromatographed on neutral alumina (activity III; 60 times the amount). A 9:1-mixture of benzene and ether elutes 1015 mg. of crystalline material which, after two recrystallizations from acetone+petroleum ether, melts at 165-167 C. (800 mg.). Optical rotation [a] =105.1 (c.=0.56). Ultraviolet spectrum: A =232 m (e=9000). Infrared spectrum: v=3600, 1674, 1617 cmr The product is a mixture of 85% of 3-oxo-4p:5p-oxido- 17fi-hydroxy-17a-methyl-A -androstene and of 3- oxo-4az5a-oxido 17B hydroxy 17a methyl-A -androstene. The ether fractions from the two chromatograms, after one crystallization from acetone+petroleum ether, yield 5.3 grams of unchanged starting material.

700 mg. of the above mixture are irradiated in 200 ml. of dioxane for 46 hours. The solution is then evaporated under vacuum. After having twice repreci pitated the crystalline crude product there are obtained 458 mg. of A -3:6-dioxo-17a-methyl-17p-hydroxy-A-nor-B-homoandrostene melting at 126-128 C. Optical rotation [a] =+79.8 (c.=0.49). Ultra-violet spectrum: A 239 m (e=8200) and 311 m (e=6700). Infrared spectrum: 11:3610. 1761, 1708 cm.-

EXAMPLE 18 Under the conditions described in Example 4 the bismethylenedioxy compound of prednisolone yields via the corresponding 4oct5oc-OXidO or 45:5,8-oxido compound (prepared as described in Example 1) the 17:20; 20:21- bis methylenedioxy compound of A -3:6:20 trioxo- 1lfi:17ar21-trihydroxy-A-nor-B-homopregnene which, on hydrolysis, furnishes free A -3:6:20-trioxo-1lpzl7az2ltrihydroxy-A-nor-B-homopregnene.

An analogous irradiation treatment of the A -3-oxo- 4oz25ocand -4 8:5p-0xido-17fl-acetoxy-19-norandrostene described in Example 16 yields A -3z6-dioxo-l7fl-acetoxy- A-nonB-homo-19-norandrostene.

EXAMPLE 19 A solution of 200 mg. of 3:6-dioxo-17fi-acetoxy-A-nor- B-homoandrostane in 10 ml. of glacial acetic acid saturated with hydrochloric acid is mixed with 2 ml. of methylmercaptan. After 48 hours the reaction mixture is worked up, to give a substantially quantitative yield of A -methylmercapto-6-oxo-l7fl-acetoxy A-nor-B-homoandrostene melting at 166-167 C. Optical rotation [u] =+124 (c.=0.67). Ultraviolet spectrumi m 319 mp. (log 6:4.02). Infrared spectrum in chloroform:

12 v=1720, 1624, 1255 cm.- On reductive desulfurization with Raney nickel the compound furnishes 6-OXO-17qtacetoxy-A-nor-B-homoandrostane melting at 114-115 C. Optical rotation [a] =+115 (c.-=0.67). Infrared spectrum in chloroform: =1723, 1692, 1255 cmr By subsequent hydrolysis this product is converted into the known 6-oxo-17a-hydroxy-A-nor-B-homoandrostane melting at 160-161 C.; optical rotation [a] =+141 (c.=0.61).

250 mg. of A -3-oxo-6:17-diacetoxy-A-nor-B-homoandrostadiene are hydrogenated in 20 ml. of benzene with 250 mg. of palladium black of 5% strength. The absorption of hydrogen is 25 ml. in 20 minutes. After the solution has been freed from the catalyst, it is evaporated under vacuum and the residue is chromatographed on 7 grams of acid alumina (activity II). mg. of crystals are isolated with a lzl-mixture of hexane and benzene, which, after two recrystallizations from etherzpentane and sublimation under high vacuum, melt at 139-140" C. Optical rotation [a] =-112 (c.-=0.49). The compound is pure 3-oxo-1718-acetoxy-A-nor-B-homoandrostane.

EXAMPLE 21 EXAMPLE 22 10 mg. of 3-oxo 17,8-acetoxyA-nor-B-homoandrostane are kept for 48 hours at room temperature in a saturated v methanolic potassium hydroxide solution. After working up, 8 mg. of 3-oxo-17,B hydroxy A nor-B-homoandrostane are obtained which, after four recrystallizations from acetone+hexane, melts at 129-130- C. Infrared spectrum in chloroform: x ,,,.'=36-20, 1725 cmr EXAMPLE 23 1.5 g. of A -3z20-dioxo 4:5 oxido 17a-acetoxypregnene in 500 ml. of dioxane are irradiated for 72 hours at 26 to 29 C. with'a low-pressure burner, and the solution is then evaporated under vacuum. The residue is dissolved in 50 ml. of alcohol, diluted with 150 ml. of'ether and agitated in a separating funnel with 10 ml. of ice-cold sodium hydroxide solution of 10% strength in 50 ml. of Water. After exhaustive extraction with sodium hydroxide solution the alkaline extracts are combined and acidified with dilute hydrochloric acid, to yield 850 mg. of crude A -3IGIZ'Q-II'iOXO 17a acetoxy- A nor B homopregnene. After recrystallization from methylene chloride+ether the pure compound melts at 198 to 199 C. Optical rotation [a] -=+76 (c. =0.945). In the'thin-layer'chromatogram (system benzene-l-methanol 9: 1) there appears a single spot.

The share that does not react with sodium hydroxide solution amounts to 0.5 g. and is unreacted starting material.

The starting material may be prepared thus:

A solution of 10 g. of A -3z20 dioxo 17oz acetoxypregnene in m1. of methylene chloride and 300ml. of methanol is mixed at 0 C. dropwise with 60 ml. of hydrogen peroxide of 30% strength and 20 ml. of sodium hydroxide solution of 10% strength and stirred for 27 hours at 0 C. The reaction mixture is then poured into ice Water andextracted with methylene chloride and ether. After washing neutral, drying and evaporating under EXAMPLE 20 vacuum there are obtained 9 g. of crude 3:20-dioxo-17uacetoxy-4:5-oxidopregnane which is used as it is, without purification, for the following step.

A solution of 5.16 g. of crude 3:20-dioxo-17a-acetoxy- 4:5-oxidopregnane in 75 ml. of tertiary amyl alcohol is mixed with 2.5 ml. of glacial acetic acidand 0.5 g. of mercury, heated to the boil, and a solution of 2.5 g. of selenium dioxide in 32 ml. of tertiary amyl alcohol is vigorously stirred in dropwise. After 14 hours, the batch is cooled, filtered through a layer of Norite and the filtrate is evaporated under vacuum. The residue is taken up in ethyl acetate and successively washed with potassium iodide solution of strength, sodium thiosulfate solution of strength, sodium carbonate solution of 10% strength and water. On evaporation of the solvent there are obtained 5.78 g. of crude A -3:20-dioxo-4z5-oxido 17a acetoxypregnene which, after filtration over alumina (activity II) and crystallization from methylene chloride-i-ether melts at 2103 to 212 C;

EXAMPLE 24 1 g. of A -3z6z2O-trioxo-17a-acetoxy-A-nor-B-homopregnene in 100 m1. of benzene is hydrogenatedin the presence of 1 g. of palladium carbon of 5% strength. When the amount of hydrogen calculated for 1 mol .has been absorbed, the catalyst is filtered off and the filtrate is evaporated. The residue constitutes 3:6:20-trioxo-l7aacetoxy-A-nor-B-homopregnane which, after crystallization from ether, melts at 221-224" C. Optical rotation [a] =+2 (c.=0.164).

In the same manner as described in Example 17, A 3z6-dioxo 17a methyl 17,8 hydroxy-A-nor-B-homoandrostene is reduced to 3:6-dioxo 17oz methyl-17,8- hydroxy-A-nor-B-homoandrostane melting at l58-160 C. Optical rotation [a] =+34 (c.=0.921).

EXAMPLE 4.15 g. of Al-3-oxo 4:5 oxido 17a methyl-1718- acetoxyandrostene in 500 ml. of dioxane are irradiated for72 hours at 26 to C. with a low-pressure burner, and the batch is then worked up as described in Example 14 fia] =-+134 (c.=0.511). In addition, 550 mg. of starting material are recovered.

23. The share soluble in sodium hydroxide solution amounts to 3.63 g. and constitutes A -3:6-dioxo 17o:

methyl, 17p acetoxy-A-nor-B-homoandrostene which, after recrystallization from methylene chloride-i-ether, melts at 20621 0 C.

Catalytic reduction of the above product in :a benzene solution in the presence of palladium carbon of 5% strength furnishes 3:6-dioxo -17a methyl-17 8-acetoxy- A-nor-B-homoandrostane.

The starting materials used for the irradiation can be prepared in the following manner:

A -3-oxo 170: methyl 17B acetoxyandrostene is oxidized with alkaline hydrogen peroxide, as described in Example 23, to yield 3-oxo-4z5 oxido 17oz methyl- 17fi-acetoxyandr0stane (melting at 1l9121 C.; from acetone-i-hexane) and then dehydrogenated with selenium dioxide to A 3-oxo-4:5-oxido-17u-methyl-17fi-acetoxyandrostene.

EXAMPLE 26 3 g. of A -3-oxo-4,5-oxido-2Ofi-acetoxypregnene in 500 ml. dioxane are irradiated for 70 hours at a temperature of 2730 -C. with a low-pressure burner, and the batch is then worked up as described in Example 23. The share The above starting material can be prepared thus:

A -3-oxo 205 hydroxypregnene (melting at 167- C.) is oxidized with alkaline hydrogen peroxide as described in Example 23, the resulting product is treated with acetic anhydride-l-pyridine, and the 3-oxo- 4:5-oxido-20,8-acetoxypregnane so formed is dehydrogenated with selenium dioxide to furnish A -3-oxo-4z5- oxido-20fl-acetoxypregnene.

EXAMPLE 27 2 g. of A -3:6-dioxo-ZOB-acetoxy-Amor-B homopregnene in 50 ml. of saturated methanolic potassium carbonate solution are boiled for 32 hours under nitrogen; the batch is then worked upas described in Example 11, to yield 1.74 g. of crude 11 -3:6-dioxo-20,6-hydroxy-A-nor-B- homopregnene which, after recrystallization from methylene chloride-tether, melts at 148l49 C. Optical rotation [a] =59 (c.=0.937).

EXAMPLE 2'8 800 mg. of A -3:6-dioxo-2Op-hydroxy-A-nor-B-homopre'gnene in 200 ml. of benzene are hydrogenated in the presence of 80 0 mg. of palladium carbon of 5% strength. When the amount of hydrogen calculated for 1 mol has been absorbed, the catalyst is filtered off and'the filtrate is evaporated under vacuum. The resulting 3:6-di0xo 20,6-hydroxy-A-nor-B-homopregnane melts at 117 to 118 C. after crystallization from ether-l-pentane.

EXAMPLE 29 1.5 g. of the lactone of A -3-ox0-4:5-oxido-l7fi-hydroxy-l7a-(fl-carboxyethyl)-androstene in 500 ml. of dioxane are irradiated for 72 hours at 2 6- to 29 C. with a low-pressure burner; the solution is then evaporated under vacuum and the residue is treated as described in Example 23. The extract obtained with sodium hydroxide solution is thela'ctone of A -3:6-dioxo-17fl-hyd'roxy-17a- (B carboxyethyl)-A-nor-B-homoandrostene; it melts after recrystallization from methylene chloride-ether at Irradiation of A -3:20-dioxo-4:S-oxidopregnene as described in the preceding examples gives rise to- A -3:6:20 trioxo-A-nor-B-homopregnene which, on catalytic reduction of the double bond in position 1:2, furnishes 3:6:20- trio-xo-A-nor-B-homopregnane.

The above starting material is accessible from progesterone by epoxidation and dehydrogenation with selenium dioxide as described in Example 23.

EXAMPLE 31 7 When the undermentioned starting materials-obtained from the corresponding A -3-ketones as described in Example 23are irradiated, there are obtained the irradiation products shown under B below:

A. Starting material B Irradiation product 15 EXAMPLE 32 A solution of 1.5 grams of A -3:20-diox0-4:5-oxid0- l7a-capronyloxypregnene in 500 cc. of dioxane is irradiated and worked up as described in Example 23, the reaction product is extracted with ice-cold dilute sodium hydroxide solution and the extract acidified with hydrochloric acid, to yield A -3:6z20-trioxo-l7a-capronyloxy- A-nor-B-homopregnene.

In an analogous manner A -3:2Odiox0-4:5-oxido-l7amethyl-pregnene can be converted into A, -3:6:2O-trioxol7a-methyl-A-nor-B-homo-pregnene.

The starting materials may be obtained by oxidizing A -3 :20-dioxo-17a-capronyloxy-pregnene and M6 :ZO-di; oxo-17m methylpregnene, respectively, with hydrogen peroxide followed by dehydrogenation with selenium dioxide as described in Example 23.

EXAMPLE 33 1.5 grams of A -3-oxo-4:5-oxido-7a-methyl 175 acetoxy-androstene in 500 cc. of dioxane are irradiated as described in Example 23, A -3:16-dioxo-7aa-methyl-17B- acetoxy-A-nor-B-homo-androstene being obtained.

In an analogous manner A -3-OXO4Z5-OXidO-7ot217ccdimethyl-17B-hydroxy-androstene is converted into A -3 6- dioxo-7aa:17a-dimethy1-17/3-hydroxy-A nor B homoandrostene.

A -3-oxo-4:5-oxido-7a-methyl-17fi-acetoxy androstene and A -3-oxo-4:5-oxido-7a:17a-dimethyl 17p hydroxyandrostene are obtained, for example, by reacting A -3- oxo-7u-methyl-l7fi-acetoxy-androstadiene and A -3-oxo- 7a:17a-dimethyl-17fl-hydroxy-androstadiene, respectively, with perben'zoic acid as described in Example 1.

EXAMPLE 34 In the catalytic hydrogenation according to Example 6 there are obtained from the compounds listed under A the hydrogenation products listed under B.

A. Starting materials A Bz6z20-trioxo-17a-capronyloxy-A-nor-B-homo-pregnene A -3:6:20-trloxo-17a-methyl-A-nor-B-homopregnene 13 -3z6-d1oxo-7aa-methyl-17B-acetoxy-A-nor-B-homo-androstene A B: 6-dloxo-7aa:17a-dimethyl-l7B-hydroxy-A-nor-B-h omo-androstene EXAMPLE 35 1.5 grams of A -3:2 dioxo-4:5-oxido l1fi2l7oc dihydroxy-Zl-acetoxy-pregnene are irradiated and worked up as described in Example 23, A -3:6:20'-trioxo-llfi:17a-dihydroxy-2l-acetoxy-A-nor-B homo pregnene being obtained and A -3:6:20-trioxo115:17041'21 trihydroxy 4 A- nor-B-homo-pregnene formed by partial hydrolysis during extraction with sodium hydroxide solution.

As described in Example 6, the above irradiation products may be converted by catalytic hydrogenation into 3:6:20-trioxo-115:17a-dihydroxy-2l-acetoxy-A nor B- homo-pregnane and 3 6:20 trioxo 11B: l7u:2.1 trihydroxy-A-nor-B-homo-pregnane, respectively.

The starting material used above is obtained from A -3:20-dioxo11fi:17a-dihydroxy-21 aceto-xy pregnadiene by reaction with perbenzoic acid as described in Example 1.

EXAMPLE 36 1.8 grams of 17:20;20:2l bis-methylenedioxy derivative of prednisolone are allowed to stand in a solution of perbenzoic acid in 100 cc. of chloroform (45 mg./cc.) for 7 days in the dark at room temperature. The reaction solution is then diluted with ether and washed in succession with aqueous potassium iodide and sodium thiosulfate solution, water, sodium bicarbonate solution andagain with water. After evaporation, 1.4 grams of a mixture containing 17:2'0;20:2l bis methylenedioxy derivative of 4oz25otand 4pz5fl-oxido-prednisolone are obtained.

1.4 grams of the. above mixture are irradiated in 170 16 cc. of dioxane for- 14 hours with a low pressure mercury lamp. After working up as described in Example 23, 420 mg. of l7:20;20:21-bis-methylenedioxy derivative of A -3z6z20-trioxo 11/8: 17 a:21-trihydroxy-A-nor-B-homopregnene are obtained; after filtration over silica gel, decoloration with animal charcoal and crystallization from a mixture of acetone and petroleum ether, the product melts at 210-230 C. with decomposition; optical rotation [a] =7 (c.=0.7). Ultraviolet spectrumt A =236 and 310 mg respectively, (e=8000 and 6080 respectively) EXAMPLE 37 A solution of 500 mg. of the ZI-acetate of A -4,5-oxido- 1704,21 dihydroxy 3,11,20 trioxopregnene (melting at 2l4218 C.) in ml. of dioxane is irradiated for 40 hours with a mercury vapour low-pressure burner while being stirred with a magnetic stirrer under a current of nitrogen at 2730 C. The solvent is then evaporated under vacuum and the residue taken u in a 1:2-mixture of alcohol and ether and agitated in a separating funnel three times with ice-cold 1% sodium hydroxide solution. The sodium hydroxide extract is acidified with dilute hydrochloric acid, extracted with methylene chloride and evaporated, toyield 310 mg. of crude A -3,6,l1,20-tetraoxo-17,21-dihydroxy A nor-B-homopregnene. (The 2l-acetate is hydrolysed during the working up). The product is purified by chromatography on 30 times its own weight of silica gel. Elution with benzene and with benzene-i-ether yields about 60 mg. of oily products; elution with ether furnishes the pure compound which, after having been recrystallised from methylene chloride-i-ether, m'elts at 184-186 C.

To prepare the starting material 4.14 g. of crude 21- acetate of 4,5 oxido 3,1l,20-trioxo-l7ot,21-dihydroxypregnane (cf. Journal of the American Chemical Society 79, page 3596 [1957]) are dissolved in 60 ml. of amylene hydrate. 2 ml. of glacial acetic acid and 0.4 g. of mercury B. Hydrogenation products 3 :6:20-triox0-171x capronyloxy-A-nor-B-homo-pregnane.

3:6:20-trioxo-l7a-methyl-A-nor-B-homopregnane.

3: 6-dloxo-7awmethyl-17B-acetoxy-A-norB-homoandrostane.

are then added and the batch is stirred and heated tothe boil, and 25 ml. of amylene hydrate containing 2 g. of selenium dioxideare dropped in. After 14 hours the batch is cooled, the amylene hydrate evaporated under vacuum, the residue taken up in ether and Washed successively with sodium thiosulphate and sodium bicarbonate solution and then with water, dried and evaporated. The residue is chromatographed on alumina, and elution is performed with a lzl-rnixture of benzene and ether to yield the desired A 4,5-oxido-17a,21-dihydroxy 3,11,20- trioxopregnene which melts at 214-218" C. after recrystallisation from methylene chloride+ether.

When the Ill-acetate of the A -4,5-oxido 6a methyl- 17,21 dihydroxy 3,11,20-trioxopregnene is irradiated in the same manner there is obtained the A -7ot-methyl- 3,6,11,20 tetraoxo 17,21 dihydroxy-A-nor-B-homo pregnene, in the enol form: A -7u-methyl-6,17,21 trihydroxy-3,11,20 trioxo-A-nor-B-homo-pregnadiene.

EXAMPLE 38 A solution of mg. of A -3-oxo- 418,5 oxido 17,8- acetoxy 1 methylandrostene in 65 ml. of dioxane is irradiated with a mercury vapour low-pressure burner (254 mg) for 2 hours and then evaporated under vacuum. The crystalline residue is twice recrystallised from aqueous methanol, whereupon it melts at 132 C., and is A -3,6 dioxo-17fi-acetoxy-l-methyl A nor-B-homoandrostene or A -3 oxo 6 hydroxy-17/3-acetoxy-lmethyl-A-nor-B-homo androstadiene respectively. For analysis a specimen is sublimed in a high vacuum at 125 C. Optical rotation [u] =-|-34 (c.=0.'61 in chloroform). Infrared spectrum: v =l725, 1660, 1612, 1255 17 cm. (in chloroform). Ultraviolet spectrum: h =249 ma. ('.==9980), 311 m (e=6600 in ethanol).

The starting material is prepared as follows:

100 mg. of A -3-oxo-17fi-hydroxy-l-methylandrostadiene are acetylated for 4 hours at 50 C. in 5 ml. of a 1:1-mixture of acetic anhydride and pyridine. The batch is evaporated under vacuum and the crude product is dissolved in benzene-l-ether 9:1 and filtered through neutral alumina of activity III. On evaporation of the solvent there results the crude A -3-ox0-17fl-acetoxy 1- methylandrostadiene. After having been twice recrystallised from acetone-l-petroleum ether the pure compound melts at 141-142" C. Optical rotation [a] =-10 (c.=().53 in chloroform). Infrared spectrum in chloroform: v =1722, 1657, 1615, 1255 cm.- Ultraviolet spectrum: A =253 111,11. (e=21500 in ethanol).

612 mg. of the above acetate in a solution of 400 mg. of perbenzoic acid in'10 ml. of chloroform is kept for 4 days in the dark at room temperature. The reaction solution is diluted with ether and successively washed with aqueous potassium iodide, sodium thiosulphate and sodium bicarbonatesolution and with water. The solvent is evaporated under vacuum and the resulting crude product is chromatographed on neutral alumina of activity II. Benzene and a 9: l-mixture of benzene and ether elute 332 mg. of crystalline A -3-oxo-4B,5-oxido-17p-acetoxyl-methylandrostene which melts at 168169 C. after two recrystallisations from acetone-l-petroleum ether. Optical rotation [a] =+170 (c.=0.98 in chlorofrom). Infrared spectrum in chloroform: v =1725, 1670, 1616, 1255 cm.- Ultraviolet spectrum: M :249 m (=9970 in ethanol).

EXAMPLE 39 350 mg. of A -3-ox0-4,5-oxido-17p-acetoxy-oestrene in 70 m1. of dioxane are irradiated for 3 hours with a mercury vapour low-pressure burner, and the solution is then evaporated under vacuum. The residue is taken up in ether and the ethereal solution washed with ice-cold 2 N- sodium hydroxide solution. The basic aqueous extracts are immediately acidified with dilute sulphuric acid and then extracted with ether. The resulting organic phase is washed with water until neutral, dried and evaporated, to leave ammonia, dilute sulphuric acid and with water. The oil 200 mg. of crystalline photoproduct, namely A -3,6-dioxo- 17,3 acetoxy-A-nor-B-homo-oestrene or A 3 oxo 6- hydroxy 17 6 acetoxy-A-nor-B-homo-oestradiene respectively. For purification the product is treated for a short time in benzene with active carbon and then dissolved in a 9:1-mixture of benzene and ether and filtered through neutral silica gel. After having been recrystallised three times from methylene chloride+rnethanol the product melts at 171-172 C. Optical rotation [u] =+l54 (c.=0.65 in chloroform). Infrared spectrum: v =1722, 1666, 1610, 1255 cmf Ultraviolet spectrum: A =238 m (e=6800); A =309 mp. (e=6480 in ethanol).

The starting material is prepared as follows:

A mixture of 500 mg. of 3-oxo-4,5-oxido-17,8-acetoxyoestrane, 25 ml. of a 10:1-solution of tertiary butanol and glacial acetic acid and 500 mg. of selenium dioxide is stirred for 2 hours and heated at the boil. The cooled solution is filtered and then evaporated under vacuum. The residue is dissolved in ethyl acetate and filtered through Celite. The ethyl acetate solution is then successively washed with ammonium hydrosulphide solution,

obtained by evaporation of the solvent is taken up in benzene and treated for a short time with active carbon. The solution is freed from the active carbon and evaporated. The resulting product is dissolved in a 9: l-mixture of benzene and ether and filtered through neutral alumina of activity III, to yield3'50 mg. of amorphous A -3-oxo- 4,5-oxido-17/9-acetoxy-oestrene. Infrared spectrum in chloroform: v =l725, 1680, 1620 cm.-

EXAMPLE 40 700 mg. of 3-oxo-4,5-oxido-17B-acetoxy-oestrane in 200 ml. of dioxane are irradiated for 2 hours with a mercury vapour high-pressure burner. The solution is then evaporated under vacuum and the residue chromatographed on 60 times its own weight of neutral silica gel. A 9: l-mixture of benzene and ether elutes 5 98 mg. of 3,6-dioxo-1713- acetoxy-A-nor-B-homo-l0-oestrane or A 3 oxo-6-hydroxy-17 3-acetoxy-A-nor-B-homo-10E-oestrene respectively. After two recrystallisations from methylene chloride-l-methanol the product melts at 152 C. Optical rotation [a], =+62 (C.=O.85 in chloroform). Infrared spectrum in chloroform: v =l720, 1642, 1605, 1260 cmf Ultraviolet spectrum: A =292 m -(e=5900' in ethanol);

A =311 m (6 9850 in 0.01 N-potassium hydroxide solution in ethanol).

The starting materialis prepared as follows:

While being stirred at 15 C. 2 ml. of aqueous 4 N- sodium hydroxide solution and then 2 ml. of perhydrol of 30% strength are added to 1 g. of 19-nortestosterone in 60 ml. The batch is kept for 4 hours at 4 C., then diluted with ethyl acetate and Washed with water until neutral. The solution is evaporated under vacuum and the resulting amorphous residue is acetylatedin 20ml. of a lzl-mixture of acetic anhydride and pyridine overnight at room temperature. The crude product obtained by evaporation under vacuum is dissolved in benzene and filtered through neutral alumina of activity II. One crystallisation of the filter residue from acetone+petroleum ether yields 750 mg. of 3-oxo-4,5-oxido-17fi-acetoxy-oestrane melting at 100-102 C. A specimen recrystallised three times melts at 104 C. Optical rotation [a] =+48 (c.=0.43 inchloroform). Infrared spectrum: u =l725=l700 (broad), 1255 cm.- (in chloroform).

EXAMPLE 41 500 mg. of 3-oxo-4,5-oxido-1,7p-hydroxy-7aa,17a-dimethyl-oestrane (melting at 138-440" C. after recrystallisation from ether) in ml. of dioxane are irradiated for 13 hours with a mercury vapour high-pressure burner. The solution is then evaporated under vacuum and the residue dissolved in a 4:1-mixture of benzene and ether and filtered through'neutral silica 'gel, to yield 400 mg. of 3,6- dioxo hydroxy 7aa,17a dimethyl A nor B- homo-oestrane or. A -3-oxo-6,l7}8-dihydroxy-7aa,17a-dimethyl-A-nor-B-homo-oestrene respectively which, after one recrystallisation from aqueous methanol, melts at 168- 169 C. Optical rotation [a]. =+83 (c.=0.67 in chloroform). Infrared spectrum in chloroform: v =3550, 1640, 1595 cmr Ultraviolet spectrum: A =293 m (5:9380).

In an analogous manner the following starting materials yield the corresponding A-nor-B-homosteroidsz' Starting material .A-nor-B-homo compound 3-ox0-4,5-oxido-l7l3-hydroxy-7aa,17a-dimethylandrostane(M.P. 154l56 0.,

from isopropyl ether 3-oro-4,5-oxido-175-hydroxy-lh-ethlnyloestrane (amorphous) 3-oxo-4,5-oxido-17B-hydroxy-17a-ethinylandrostene (M.P. l68174 0., from methylene chloride-l-ether) 3,6-dioxo-17B-hydroxy-7aa, l7a-dimethyl-A-nor-B-homoandrostane 0 respectively A B-0x04), l7fl-dihydroxy-7aa, 17a-dirnethyl-A-nor-B- homo-androstene (M.P. 162163 0., from isopropyl ether).

3,6-dioxo-176-hydr0xy-lh-ethlnyLA-nor-B-homoandrostane or A 43- oxo-6, 17B-dihydroxy 17a-ethinyl-A-nor-B-homoandrostene (M.P. MiG-168 0., from methylene chloride plus ether).

Starting material A-nor-B-homo compound 3-oxo-4,5-oxido-17B-acetoxy-17a-ethinylandrostane (M.P. 168-174! 0.) 3,6-dioxo-17fl-acetoxy-lM-ethinyl-A-nor-B-homoandrostane and A -3- oxo-G-hydroxy-17fl-aeetoxy-lh-ethinyl-Amor-B-homoandrostene M P. 176182 0., from methylene chloride plus ether).

3-oxo-4,5-oxido-17B-decanoyloxyoestraue (oil) 3,6-diox-17B-decanoyloxy-A-nor-B-homooestrane and A -3-oxo-6- hydroxy-17B-decan0yloxy-A-nor-B-homooestrene (M.P. 5051 0., irom pentane).

3-oxo-4,5-oxido-17B-(fi-phenylpropionyloxy)-oe5trane (M.P. Bil-134 0.) 3,6-dioxo-17B-(B-phenylpropionyloxy)-A-nor-B-homooestrane and p A -3-oxo-6-hydroxy-l 7,3-(x-phenylpropionyloxy) -A-n0r-B -homooestrene (M.P. 98-99 0., from ether plus pentane).

3-0140-4,5-oxide-l7fl-hydroxy-17a-methylocstrane 3,6-dioxo-l7B-hydroxy-17a-methyl-A-nor-B-homooestrane and A -3- oxo-G,17B-dihydroxy-lh-methyl-A-nor-B-homooestrene (M.P. 159l61 0., from methylene chloride plus ether).

3-oxo-4,5-oxido-175-isobutyloxy-androstane 3,6-dioxo-17B-isobutyryloxy-A-nor-B-homoandrostane and N-B-oxo-fihydroxy-17/3-isobutyryloxy-Aenor-B-homoandrostene (M.P. 141- 144" 0., from ether).

3,6-dioxo-17B-n-valerianyloxy-A-nor-B-hon1oandrostane and N-Ii-oxo- G-hydroxy-17fi-n-valerianyloxy-A-nor-B-homoandrostene (M.P. 90 91 0., from ether plus pentane).

3-oxo-4,5-oxido-17fl-undecenoyloxy-audrostane .1. 3,6-dioXo-l7B-undecenoyloxy-A-norB-homoandrostane and A -3-oxo- 6 hydroxy-17B-undecenoyloxy-A-nor-B-homoaudrosteue (M.P. 51-

52 0., from pentane).

3-0xo-4,5-oxido-17B-n-valerian yloxy-androstane 3-oxo-4,5-oxido-7aa, 17a-dlmethylandrostane (M.P. 151153 0.) A -3-oxo-6, 17B-dihydroxy-7aa,17a-dimethy1-A-nor-B-homoandrostene (M.P. 162164 0.).

A 3-oxo-fi-hydroxy-20-ethylenedioxy-A-nor-B-homopregnene (M.P.

160161 0.); A 3,20-dioxo-fi-hydroxy-A-nor-B-homopregnene (M.P.

3-0x04,5 oxido--ethylenedioxypregnane (M.P. 217223 C.)

137-138" 0.); A-3,20-dioxo-6-acetoxy-A-nor-B-homopregnene (M.P.

The above starting materials are prepared from the solutions are washed with Water, dried and evaporated corresponding A -3-ketones by the method described in under vacuum. After repeated recrystallization from 21 Example 40. mixture of methylene chloride and isopropyl ether there are obtained 1.56 g. of pure 3,6-dioxo-20-ethylene dioxy- EXAMPLE 42 21-hydroxy-A-nor-B-homo-pregnane melting at l64165 Amixture of 1.2 g. of A -3-oxo-6,17fi-dihydroxy-17u- C methylandrostene, 1 ml. of hydazine hydrate and 100 ml. 1 g, of th l tt r co d i h k ith 20 1, of of ethanol is refluxed for 4 hours. The cooled reaction ox n-free 70% f i id (d t d t 100 c with mixture is evaporated t dryness under u T nitrogen) for 20 minutes under nitrogen at 60 c. The PYfaZOIle defivativfi thus formed is crysta liz Once resulting solution is mixed at 0 C. with a solution of 34 from aqueous methanol, to yield 620 mg. of crystals meltg. of potassium bicarbonate in 200 ml. of water and exing at 210 to 212 C. Optical rotation [a]=+20 haustively extracted by agitation with methylene chloride. (c.-=0.50, in chloroform). Ultraviolet spectrum The combined methylene chloride solutions are washed with water, dried and chromatographed on 20 g. of silica A :226 m max gel (containing 5% of moisture). The considerably con- In flhtanol). Infrared spectrum In N11101: centrated methylene chloride eluates are mixed with isomax 1628 Weakpropyl ether, whereupon 3,6,20-trioxo-2l-hydroxy-A-nor- EXAMPLE 43 B- homopregnane crystallizes out; it melts at 132136 C.

. Yield: 710 mg.

P e y w- The starting material used above is obtained from the pregnane in 255 ml. of dioxane are irradiated for 13 hours known As 3,zobisethylenedioxyal acetoxypregnene by wltoh a 'P burner at a temperature of 7 to partial deketalization in 3-position With a mixture of para- 18 C. The solution 18 then evaporated, to leave as residue t l lf i acid and acetic acid in acetone The Crude l f Q Y 9 sulting monoketal is mixed with hydrogen peroxide in the h qp gn t0 P y 1t, 1t 15 1n meth1ne presence of alkali and the hydrolized 21-acetoxy group is ChlOrlde f chfomafogfaphed 011 slllca gel finally reacetylated with acetic anhydride in the presence 5% of moisture). The residue of the methylene chloride 0 f pyridine eluates 1S recfystalhled ffomgmethanol to yield t P F Irradiation as described above may also be performed product meltlng at 12 6l3 1 C. The mother liquor 18 with 3 OX0 45 0XidO 2O ethy1enedi0Xy 2l.hydroxypreg evaporated, and the residue is dissolved in ml. of methname, whereupon 20- 1 -21hy anol, mixed with a solution of 1 g. of potassium ea A-nor-B- homopregnane is obtained as irradiation product. bonate m 20 ml. of water and hydrolyzed by bemg boiled 5 for 2 hours under reflux. The solution is evaporated under EXAMPLE 44 vacuum and the residue agitated with ethyl acetate. The 5 g, of 3-QXO-4,5-oxide-20--ethylenedioxypregnane in ethyl acetate solutions are combined, washed with water, 900 ml. of dioxane are irradiated for 48 hours with a dried and evaporated under vacuum. To purify the hyhigh-pressure burner at 17 to 18 C. The solution is evap drolysis product the residue is taken up in a 1:3-mixture orated and the residue dissolved in a 1:3-mixture of methof methylene chloride and ether and repeatedly agitated ylene chloride and ether, and the solution is repeatedly wlth ice-cold 2 N sodium hydroxide solution. The comagitated with ice-cold 8% sodium hydroxide solution. biped sodium hydroxide extracts are adjusted at 0 C. The combined sodium hydroxide extracts are mixed at with phosphoric acid to pH=4 to 5 and exhaustively ex- 0 C. with phosphoric acid to pH=4 to 5 and the whole tracted Wlth methylene chloride. The methylene chloride is exhaustively extracted with methylene chloride. The

21 methylene chloride extracts are washed with water, dried and evaporated under vacuum. On addition of ethanol and further evaporation of the methylene chloride, 3,6-dioxo- 20-ethylenedioxy-A-nor-B-homopregnane crystallizes out. Recrystallization from a mixture of methylene chloride and isopropyl ether furnishes 2.2 g. of the pure compound metling at 160 to 162 C.

2 g. of the compound thus obtained are mixed with 30 ml. of 80% acetic acid and heated for 30 minutes on a boiling water bath. The solution is then evaporated under vacuum, the residue is dissolved in a 1:3-mixture of methylene chloride and ether, and the solution is washed with water, dried and evaporated under vacuum. The residue is dissolved in methylene chloride and chromatographed on 20 g. of silica gel (containing 5% of moisture). The methylene chloride solutions are evaporated and the residue is recrystallized from a mixture of methylene chloride and isopropyl ether, to yield 1.6 g. of 3,6, 20-trioxo-A-nor-B-homopregnane melting at 137-138 C.

1 g. of the last-mentioned compound is dissolved in 2 ml. of pyridine, 2 ml. of acetic anhydride are added and the whole is kept for 4 days at room tempreature. The solution is then mixed with ice, kept for 1 hour at 20 C. and evaporated under vacuum. The residue is chromatographed first with methylene chloride and then with a 99:1-mixture of methylene chloride and tertiary butanol on 20 g. of silica gel; the first methylene chloride fractions may still contain some starting material. The further fractions eluted with methylene chloride and a 99:1- mixture of methylene chloride and tertiary butanol are combined and evaporated. The residue is recrystallized from hexane+pentane, to yield 800 mg. of A -3,20-dioxo- 6-acetoxy-A-nor-B-homopregnene melting at 95 to 97 C.

The above-mentioned starting material is accessible from the known A -313-acetoxy-20-ethylenedioxypregnene by alkaline hydrolysis, oxidation of the resulting A -3- hydroxy-compound with chromium trioxide to A -3-oxo- 20-ethylenedioxypregnene, followed by treatment with hydrogen peroxide in the presence of sodium hydroxide solution.

EXAMPLE 45 700 mg. of 3-OX0-4,5-0Xid016a,l7ct-dihYdI'OXY-20-6thYlenedioxypregnane in 140 ml. of dioxane are irradiated for 13 hours with a high-pressure burner at 20 C. The solution is evaporated and the residue dissolved in ether and repeatedly agitated with ice-cold 2% sodium hydroxide solution. The aqueous extracts are combined, adjusted at C. with phosphoric acid to pH=4 to and exhaustively extracted by agitation with methylene chloride. The methylene chloride solutions are combined, washed with water, dried and evaporated under vacuum. The resulting 3,6-dioxo-16a,17ot-dihydroxy-20 ethylenedioxy A nor- B-homopregnane (360 mg.) is dissolved in 30 ml. of pure acetone, heated to a gentle boil, mixed with 3 drops of concentrated hydrochloric acid, heated for another 2 minutes and then kept for 24 hours at C. On dilution with ice water there are obtained crystals which are suctioned 01f and dried. For purification-they are dissolved in methylene chloride and chromatographed on 2 g. of silica gel (containing 5% of moisture). The residue from the methylene chloride eluates is recrystallized from methylene chloride-i-isopropyl ether, to yield 280 mg. of 3,6,20-trioxo 160:,17a dihydroxy A-nor-B-homopregnane-16,17-acetonide melting at 204 to 205 C.

The starting material used above is obtained from A fi-3B-acetoxy-ZO-ethylenedioxypregnadiene by alkaline hydrolysis and Oppenauer oxidation to A -3-oxo-20- ethylenedioxypregnadiene, oxidation with hydrogen peroxide to the corresponding 4,5-oxido compound, followed by hydroxylation of the 16,17-double bond with osmium tetroxide.

EXAMPLE 46 A solution of 2.168 g. of 3-oxo-4,5-oxido-11/3-hydroxy- 17a,20;20,21-bismethylenedioxypregnane (mixture of the 22 40,5aand 45,5,9-0Xid'o compounds) in 500' ml. of pure dioxane is vigorously stirred at 18 to 22 C. while being irradiated with a mercury vapour high-pressure lamp until a specimen of the reaction mixture reveals that the infrared absorption has reached a maximum at 6.08 and 6.24 This is generally the case after 8 to 16 hours. The solution is then evaporated under vacuum, the pale yellowish residue is dissolved in 320 ml. of benzene and the crude product is absorbed on g. of silica gel while being flushed with 80 ml. of benzene. Successive elution is performed with 4 portions each of benzene, benzene-l-ethyl acetate (95:5) and benzene-l-ethyl acetate (:15), 400 cc. of solvent being used for every fraction. The resulting photoisomerization product is found in the last benzene +ethyl acetate (:5) fractions and in the first benzene +ethyl acetate (85:15) fractions. The crystalline evaporation residues yield after recrystallization from methylene chloride+ether a total of 0.967 g. of 3,6-dioxo-ll-flhydroxy l7,20;20,21 bismethylenedioxy A nor B- homopregnane in colorless, coarse rhombohedrons melting at 193-196 C.

To eliminate the protective groups in the side chain, a solution of 0.420 g. of 3,6-dioxo-11,8hydroxy-17oc,20;20, 2l-bismethylenedioxy-A-nor-B-homopregnane in 25 ml. of tetrahydrofuran is mixed at 15 C. within 30 minutes with 75 ml. of 2.66-molar aqueous perchloride acid. The solution is stirred for 16 hours at 20 C., then cooled with ice and neutralized with 250 ml. of N-sodium bicarbonate solution and the hydrolysis product is agitated with methylene chloride+ether (1:2). The extracts are washed with 0.4 N-sodium bicarbonate solution and with water, dried over sodium sulfate and evaporated to yield 0.372 g. of a crystalline crude product; for purification it is dissolved in ml. of benzene and the solution is filtered through a column of 10 g. of silica gel prepared with benzene, while being further eluated with benzene+ethyl acetate mixtures 95:5, 85:15 and 50:50. On evaporation under vacuum the filtrates are extensively freed from benzene and ethyl acetate and yield a total of 0.315 g. of pure 3,6,20 trioxo '1 1fi,17oz-2l trihydroxy A nor B- homopregnane in almost colorless crystals melting at 137- When the'17,20;20,2l-bismethylenedioxy group is split with 70% perchloric acid in glacial acetic acid at room temperature (2-3 hours), A 3,20 dioxo-6-acetoxy-11fi,

17a,2l-trihydroxy-A-nor-B-homopregnane is obtained, in addition to the corresponding 21-acetate, which can be hydrolyzed as described above with dilute perchloric acid in tetrahydrofuran to 3,6,20-trioxo-11;8,17a,21-trihydroxy- A-nor-B-homopregnane and to its 21-acetate respectively.

The starting material used in the above example can be prepared as follows:

In the course of 30 minutes, at l5 to 20 C., 62.5 ml. of N-aqueous tetrarnethylammonium hydroxide and 31.25 ml. of 30% hydrogen peroxide are added simultaneously with stirring from two separate dropping funnels to a solution of 2.528 g. of A -3-oxo-11B-hydroxy- 17u,20;20,21-bismethylenedioxy-pregnene in 532 ml. of methanol previously cooled to 15 C. After having kept the solution for 24 hours at 10 C., the alkali is neutralized at 15 C. with 62.5 ml. of 1.5 N-orthophosphoric acid; the reaction solution is poured over a mixture of 25( g. of ice and 500 ml. of ice-cold water and extracted by agitation with ice-cold methylene chloride. The ice-cold extracts are washed with water, combined, dried over sodium sulfate and evaporated under vacuum, towards the end with addition of ether. The ether solution is freed from methylene chloride and yields 2.035 g. of crystalline pure 3-oxo-4,5-oxido-11B-hydroxy-l7a,20;20, 21-bismethylenedioxypregnane (a mixture of the 4oc,5aand 4,8,5Boxido compounds) melting at 202-286 C.

The starting materials listed below, obtained by known processes, yield in an analogous manner the corresponding A-nor-B-homosteroids:

Starting materials A-nor-B-homo compounds 3,6-dioxo-17a,20;20,21-hismethylenedioxy-A-nor-B- homo-MOU-pregnene (M.1 224-226 0.). 1 A

l 3-oxo4,5-oxido-17a,2O:20,21-bismethylenedioxy-A( )-pregncne gggg ggg ifgggg zfigf gggggi 3,6,20-tri0xo-17whydroxy-21-acetoxy-A-nor-B-homo- MOQ-pregnene.

3,6,11-trioxo-17,20;20,21-bismethy1enedioxy-A-nor-B- horrgo-n -pregnene (M.P 217220 0.). 3,1Idiom-4,5-oxido-l7,20;20,2l-bismethylenedioxy-A -pregnene (M-P. 2es-273 o.) "225:3:fif zfif lfgfla gf;gfi gggfiamg 3,11,20-trioxo-6,21-diacetoxy-17a-hydroxy-A-n0r-B- homo-A fi-pregnadiene.

EXAMPLE 47 EXAMPLE 51 a 1000 tablets each containing 5 mg. of the active sub- 1000 lmguettes each contalning 1 mg. of the active substance. Ingredients: stance. Ingredients:

G. G. 3,6,20-trioxo-l7fi-acetoxy-A-nor B homo preg- A -3:6:20-trioxo-1lfizl7az2l-trihydroxy A nor-B- nane 5.0 homo-pregnene 1 Lactose 70.0 Lactose 100 Gelatin 3.0 Saccharose 229 Wheat starch 40.0 Stearic acid 3 Arrowroot 15- a 17 Magnesium stearate 0.7 Talc 350 140 0 Procedure.-The mixture of the active substance with lactose is moistened with an aqueous solution of saccha- Pr0cedure.--The mixture of the active ingredient, lac- 0 rose and granulated in the. usual manner. After being tose and wheat starch is moistened with a gelatine solution of 10% strength to form a slightly plastic mass, and then granulated in the usual manner. After being dried at C., the mass is brought into the usual grain size by being passed through a sieve. Arrowroot, magnesium stearate and talc are added to the dried mass and the mixture is then compressed into tablets of 7 mm. in diameter.

EXAMPLE 48 1000 tablets each containing 1 mg. of the active substance. Ingredients:

EXAMPLE 49 p 1000 tablets each containing 1 mg. of the active substance. Ingredients:

A -3:6-dioxo-17a-methyl-1713-hydroxy-A nor B- homo-androstene 1.0 Lactose 50.0 Colloidal silicic acid with hydrolysed starch 5.0 Wheat starch 20.0 Arrowroot 9.0 Magnesium stearate 0.7 Talc 4.3

Procedure-Analogous to that described in Example EXAMPLE 50 In the manner described in Examples 47 to 49 tablets can be prepared each containing 25 mg. of the lactone of A -3z6-dioxo-l7fi-hydroxy 17a-(B-carboxy-ethyl)-A- nor-B-homo-androstene or 1 to 5 mg. of the active products described in the following examples.

dried, the sieved granulate is mixed with stearic acid and talc and then compressed into linguettes.

EXAMPLE 52 100 oil ampoules each containing 25 mg./ml. of the active substance. Ingredients:

3 6-dioxo-17 8-acetoxy-A-nor-B-homo-androstane-2.5 g. Benzyl alcohol10 ml. Sesame oil-- ml.

Pr0cedure.The active ingredient is dissolved in benzyl alcohol and the stirred solution diluted with hot sterilized sesame oil. 1 ml. of this solution containing the ingredients in the above given amounts is filled in ampoules which are sterilized at 160 C. for 1.5 hours.

EXAMPLE 5 3 oil ampoules each containing 10 mg./ml. of the active substance. Ingredients:

A 3:6 dioxo 17 8-acetoxy-A-nor-B-homo-androstene Neutral sterilized sesame oill00 ml.

Pr0cedure.-In a 100 ml. flask the active substance is dissolved in 5 to 10 ml. of pure acetone and the acetone evaporated. The residue is then dissolved in the sesame oil which has been purified and sterilized by heating it to 180 C. for two hours. The solution obtained is filtered through a glass filter and 1 ml. of the filtrate is filled in ampoules which are sterilized at C. for 1.5 hours.'

EXAMPLE 54 In the manner described in Examples 52 and 5 3 oil ampoules can be prepared each containing 10 to 25 mg. of

1000 tablets of an anabolic preparation containing 3,6 dioxo hydroxy 7aa,17ot dimethyl-A-nor-B- homo-oestrane are manufactured from the following ingredients:

Grams 3,6 dioxo 17,8-hydroxy-7aa,17a-dimethyl-A-nor- B-homo-oestrane 1.0 Lactose 74.0 Gelatine 3.0 Wheat starch 40.0 Arrowroot 15.0 Magnesium stearate 0.7 Talcum 6.3

Formulatiom-The active principle is mixed with lactose and wheat starch and moistened with a gelatine solution to form a slightly plastic dough which is then granulated in the known manner, dried at 40 C. and reduced to the conventional particle size by being sifted. The dry granulate is mixed with arrowroot, magnesium stearate and talcum, and the whole is mixed and pressed to form tablets of 7 mm. diameter.

Another especially suitable oral anabolic medicament form is the following:

1000 tablets containing 3,6-dioxo-17p-hydroxy-7au,17adimethyl-A-nor-B-homo-oestrane.

Grams 3,6 dioxo 17B hydroxy-7aa,17a-dimethyl-A-nor- B-homo-oestrane 0.1

Lactose 50.0

Colloidal silicic acid with hydrolysed starch 5.0 Arrowroot 9.0 Wheat starch 20.9 Magnesium stearate 0.7 Talc 4.3

The tablets are made in a manner similar to that set forth above.

For parenteral use there are especially suitable oil ampoules as follows:

100 oil ampoules each containing 0.05 mg./ml. of the active substance.

Ingredients:

3,6 dioxo 17B hydroxy 17aoz,17oc dimethyl-A-nor-B- homo-oestrane 0.005 gram Neutral sesame oil100 ml.

They are prepared in a manner similar to that set forth in previous examples.

In an analogous manner anabolic preparations containing 3,6 dioxo l7 fl-hydroxy-7aa-17a-dimethyl-A-nor-B- homo-androstene can be manufactured.

EXAMPLE 56 100 oil ampoules of an anabolic preparation for parenteral administration, each containing 25 mg. per ml. of A -3,6-dioxo-17/8-acetoxy-1-methyl-A-nor-B-homoandrostene are manufactured from the following ingredients:

A 3,6 dioxo 17,8 acetoxy 1 methyl-A-nor-B-homoandrostene2.5 g.

Benzyl alcohol-10 ml.

Sesame oi190 ml.

The active principle is dissolved in the benzyl alcohol and the stirred solution is diluted with sesame oil sterilised at an elevated temperature. 1 ml. of this solution, which contains the above proportions of the ingredients, is charged into arnpoules which are then sterilised for 1 /2 hours at 160 C.

In an analogous manner anabolic preparations can be prepared which are suitable for parenteral administration and contain as active principle A -3,6-dioxo-17,3-acetoxy- A-nor-B-homo-oestrene or 3,6-dioxo-17fl-acetoxy-A-nor- B-homo-lOg-oestrane.

26 EXAMPLE 57 1000 tablets of a gestagenic pharmaceutical preparation each containing 5 mg. of 3,6-dioxo-17B-hydroxy-17aethinyl-A-nor-B-homo-oestrane are manufactured from the following ingredients:

Grams 3,6 dioxo-17/3-hydroxy-17a-ethinyl-A-nor-Bhomooestrane 5.0

Lactose 70.0

Gelatine 3.0 Wheat starch 40.0 Arrowroot 15.0 Magnesium stearate 0.7 Talcum 6.3

Formulation.-As described in Example 55.

In an analogous manner gestagenic preparations for oral administration, containing 3,6-dioxo-17p-hydroxy-17aethinyl-A-nor-B-homo-androstane as active principle, can be manufactured.

EXAMPLE 58 1000 tablets of a pharmaceutical preparation for use as an antiphlogistic, each containing 1 mg. of A -3,6,11,20- tetraoxo 17a,21-dihydroxy-A-nor-B-homo-pregnene, are manufactured from the following ingredients:

Grams A -3,6,11,20-tetraoxo-17a,21 dihydroxy-A-nor B-homopregnene 1.0 Lactose 53.0

Gelatine 1.0 Wheat starch 39.5 Magnesium stearate 0.3 Talcum 5.2

Formulati0n.--As described in Example 55.

EXAMPLE 59 1000 tablets of an anabolic preparation each containing 5 mg. of 3,6-dioxo-17p-hydroxy-17a-methyl-A-nor- B-homo-androstane are manufactured from the following ingredients:

What is claimed is:

1. Process for the manufacture of A-nor-B-homosteroids which comprises irradiating a member selected from the group consisting of a 3-oxo-4a,5a-oxido-steroid, a 3-oxo-4fi,5fi-oxido-steroid and the l-dehydro derivative thereof with ultraviolet light.

2. Process according to claim 1, wherein irradiation is performed in an organic solvent.

3. Process according to claim 1, wherein irradiation is performed in dioxane.

References Cited UNITED STATES PATENTS 3,013, 027 12/1961 Ruzicka et al. 204158 HOWARD S. WILLIAMS, Primary Examiner US. Cl. X.R. 260340.9, 343.6 

